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Smooth Normative Brain Mapping of Three-Dimensional Morphometry Imaging Data Using Skew-Normal Regression
Tensor-based morphometry (TBM) aims at showing local differences in brain volumes with respect to a common template. TBM images are smooth, but they exhibit (especially in diseased groups) higher values in some brain regions called lateral ventricles. More specifically, our voxelwise analysis shows both a mean–variance relationship in these areas and evidence of spatially dependent skewness. We propose a model for three-dimensional imaging data where mean, variance and skewness functions vary smoothly across brain locations. We model the voxelwise distributions as skew-normal. We illustrate an interpolation-based approach to obtain smooth parameter functions based on a subset of voxels. The effects of age and sex are estimated on a reference population of cognitively normal subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set and mapped across the whole brain. The three parameter functions allow transforming each TBM image (in the reference population as well as in a test set) into a normative map based on Gaussian distributions. These subject-specific normative maps are used to derive indices of deviation from a healthy condition to assess the individual risk of pathological degeneration.
Biophysical effects and neuromodulatory dose of transcranial ultrasonic stimulation.
Transcranial ultrasonic stimulation (TUS) has the potential to usher in a new era for human neuroscience by allowing spatially precise and high-resolution non-invasive targeting of both deep and superficial brain regions. Currently, fundamental research on the mechanisms of interaction between ultrasound and neural tissues is progressing in parallel with application-focused research. However, a major hurdle in the wider use of TUS is the selection of optimal parameters to enable safe and effective neuromodulation in humans. In this paper, we will discuss the major factors that determine the efficacy of TUS. We will discuss the thermal and mechanical biophysical effects of ultrasound, which underlie its biological effects, in the context of their relationships with tunable parameters. Based on this knowledge of biophysical effects, and drawing on concepts from radiotherapy, we propose a framework for conceptualising TUS dose.
Considerations and recommendations from the ISMRM diffusion study group for preclinical diffusion MRI: Part 2-Ex vivo imaging: Added value and acquisition.
The value of preclinical diffusion MRI (dMRI) is substantial. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages including higher SNR and spatial resolution compared to in vivo studies, and enabling more advanced diffusion contrasts for improved microstructure and connectivity characterization. Another major advantage of ex vivo dMRI is the direct comparison with histological data, as a crucial methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work represents "Part 2" of a three-part series of recommendations and considerations for preclinical dMRI. We describe best practices for dMRI of ex vivo tissue, with a focus on the value that ex vivo imaging adds to the field of dMRI and considerations in ex vivo image acquisition. We first give general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in specimens and models and discuss why some may be more or less appropriate for different studies. We then give guidelines for ex vivo protocols, including tissue fixation, sample preparation, and MR scanning. In each section, we attempt to provide guidelines and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should lie. An overarching goal herein is to enhance the rigor and reproducibility of ex vivo dMRI acquisitions and analyses, and thereby advance biomedical knowledge.
Considerations and recommendations from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 3-Ex vivo imaging: Data processing, comparisons with microscopy, and tractography.
Preclinical diffusion MRI (dMRI) has proven value in methods development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages that facilitate high spatial resolution and high SNR images, cutting-edge diffusion contrasts, and direct comparison with histological data as a methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work concludes a three-part series of recommendations and considerations for preclinical dMRI. Herein, we describe best practices for dMRI of ex vivo tissue, with a focus on image pre-processing, data processing, and comparisons with microscopy. In each section, we attempt to provide guidelines and recommendations but also highlight areas for which no guidelines exist (and why), and where future work should lie. We end by providing guidelines on code sharing and data sharing and point toward open-source software and databases specific to small animal and ex vivo imaging.
Prevalence of dementia risk factors in the Oxford Brain Health Clinic.
With promising disease-modifying therapies (DMTs) emerging and good evidence to support risk reduction in the delay of dementia onset and progression, it is important to understand the profile of patients attending memory assessment services to estimate what proportion of patients might benefit from different types of interventions. The Oxford Brain Health Clinic (OBHC) is a psychiatry-led, clinical-research service that offers memory clinic patients detailed clinical assessments and equal access to research opportunities as part of their secondary care pathway. In this work, we describe the characteristics of OBHC patients in terms of demographics, diagnoses and prevalence of potentially modifiable risk factors compared with a cohort of healthy volunteers and the average memory clinic population. Our results suggest that high research consent rates (91.5%) in the OBHC resulted in a highly representative cohort of the clinical population. Based on Lecanemab trial inclusion criteria, 24.6% of the OBHC population may be suitable for further investigation into DMTs. Furthermore, 67.4% of OBHC patients have at least one potentially modifiable risk factor that may benefit from lifestyle interventions, particularly those focused on depression, sleep and physical activity.
How and why eLife selects papers for peer review.
When deciding which submissions should be peer reviewed, eLife editors consider whether they will be able to find high-quality reviewers, and whether the reviews will be valuable to the scientific community.
Effects of the KCNQ (Kv7) Channel Opener Ezogabine on Resting-State Functional Connectivity of Striatal Brain Reward Regions, Depression and Anhedonia in Major Depressive Disorder: Results from a Randomized Controlled Trial.
BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests targeting specific subtypes of depression and understanding the underlying brain mechanisms can improve treatment outcomes. This study investigates the potential of the potassium KCNQ (Kv7) channel opener ezogabine to modulate the resting-state functional connectivity (RSFC) of the brain's reward circuitry and alleviate depressive symptoms, including anhedonia, a core feature of MDD. METHODS: A double-blind, randomized, placebo-controlled clinical trial in individuals aged 18 to 65 with MDD compared daily dosing with ezogabine (n=19) to placebo (n=21) for five weeks. Functional magnetic resonance imaging (fMRI) assessed RSFC of the brain's key reward regions (ventral caudate, nucleus accumbens) at baseline and post-treatment. Clinical symptoms were measured using the Snaith-Hamilton Pleasure Scale (SHAPS), Montgomery-Åsberg Depression Rating Scale (MADRS), and other clinical symptom scales. RESULTS: Ezogabine significantly reduced RSFC between the reward seeds and the posterior cingulate cortex (PCC)/precuneus compared to placebo, which was associated with a reduction in depression severity. Improvements in anhedonia (SHAPS) and depressive symptoms (MADRS) with ezogabine compared to placebo were also associated with decreased connectivity between the reward seeds and mid/posterior cingulate regions (MCC, PCC, precuneus). CONCLUSIONS: The findings suggest that ezogabine's antidepressant effects are mediated through modulation of striatal-mid/posterior cingulate connectivity, indicating a potential therapeutic mechanism for KCNQ-targeted drugs for MDD and anhedonia. Future studies should validate these results in larger trials. CLINICALTRIALS: gov identifier: NCT03043560.
Intrinsic and extrinsic control impact motivation and outcome sensitivity: the role of anhedonia, stress, and anxiety
AbstractBackgroundMotivated behaviors vary widely across individuals and are controlled by a range of environmental and intrinsic factors. However, due to a lack of objective measures, the role of intrinsic v. extrinsic control of motivation in psychiatric disorders remains poorly understood.MethodsWe developed a novel multi-factorial behavioral task that separates the distinct contributions of intrinsic v. extrinsic control, and determines their influence on motivation and outcome sensitivity in a range of contextual environments. We deployed this task in two independent cohorts (final in-person N = 181 and final online N = 258), including individuals with and without depression and anxiety disorders.ResultsThere was a significant interaction between group (controls, depression, anxiety) and control-condition (extrinsic, intrinsic) on motivation where participants with depression showed lower extrinsic motivation and participants with anxiety showed higher extrinsic motivation compared to controls, while intrinsic motivation was broadly similar across the groups. There was also a significant group-by-valence (rewards, losses) interaction, where participants with major depressive disorder showed lower motivation to avoid losses, but participants with anxiety showed higher motivation to avoid losses. Finally, there was a double-dissociation with anhedonic symptoms whereby anticipatory anhedonia was associated with reduced extrinsic motivation, whereas consummatory anhedonia was associated with lower sensitivity to outcomes that modulated intrinsic behavior. These findings were robustly replicated in the second independent cohort.ConclusionsTogether this work demonstrates the effects of intrinsic and extrinsic control on altering motivation and outcome sensitivity, and shows how depression, anhedonia, and anxiety may influence these biases.
Reward-related self-agency is disturbed in depression and anxiety
Background The sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of reward-dependent agency perception in an in-person and online cohort. Methods The in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort implementation for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency. Results All subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive feedback-dependent agency compared to healthy controls. Finally, in our online sample, we found that higher self-agency following negative-loss feedback was associated with worse anhedonia symptoms. Conclusion Together this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety.
On what motivates us: a detailed review of intrinsic v. extrinsic motivation.
Motivational processes underlie behaviors that enrich the human experience, and impairments in motivation are commonly observed in psychiatric illness. While motivated behavior is often examined with respect to extrinsic reinforcers, not all actions are driven by reactions to external stimuli; some are driven by 'intrinsic' motivation. Intrinsically motivated behaviors are computationally similar to extrinsically motivated behaviors, in that they strive to maximize reward value and minimize punishment. However, our understanding of the neurocognitive mechanisms that underlie intrinsically motivated behavior remains limited. Dysfunction in intrinsic motivation represents an important trans-diagnostic facet of psychiatric symptomology, but due to a lack of clear consensus, the contribution of intrinsic motivation to psychopathology remains poorly understood. This review aims to provide an overview of the conceptualization, measurement, and neurobiology of intrinsic motivation, providing a framework for understanding its potential contributions to psychopathology and its treatment. Distinctions between intrinsic and extrinsic motivation are discussed, including divergence in the types of associated rewards or outcomes that drive behavioral action and choice. A useful framework for understanding intrinsic motivation, and thus separating it from extrinsic motivation, is developed and suggestions for optimization of paradigms to measure intrinsic motivation are proposed.
Altered hippocampus and amygdala subregion connectome hierarchy in major depressive disorder
AbstractThe hippocampus and amygdala limbic structures are critical to the etiology of major depressive disorder (MDD). However, there are no high-resolution characterizations of the role of their subregions in the whole brain network (connectome). Connectomic examination of these subregions can uncover disorder-related patterns that are otherwise missed when treated as single structures. 38 MDD patients and 40 healthy controls (HC) underwent anatomical and diffusion imaging using 7-Tesla MRI. Whole-brain segmentation was performed along with hippocampus and amygdala subregion segmentation, each representing a node in the connectome. Graph theory analysis was applied to examine the importance of the limbic subregions within the brain network using centrality features measured bynode strength(sum of weights of the node’s connections),Betweenness(number of shortest paths that traverse the node), andclustering coefficient(how connected the node’s neighbors are to one another and forming a cluster). Compared to HC, MDD patients showed decreased node strength of the right hippocampus cornu ammonis (CA) 3/4, indicating decreased connectivity to the rest of the brain, and decreased clustering coefficient of the right dentate gyrus, implying it is less embedded in a cluster. Additionally, within the MDD group, the greater the embedding of the right amygdala central nucleus (CeA) in a cluster, the greater the severity of depressive symptoms. The altered role of these limbic subregions in the whole-brain connectome is related to diagnosis and depression severity, contributing to our understanding of the limbic system involvement in MDD and may elucidate the underlying mechanisms of depression.
Intrasubject functional connectivity related to self‐generated thoughts
AbstractIntroductionIn psychiatric research, functional connectivity (FC) derived from resting‐state functional MRI (rsfMRI) is often used to investigate brain abnormalities in psychiatric disorders. This approach assumes implicitly that FC can recover reliable maps of the functional architecture of the brain and that these profiles of connectivity reflect trait differences underlying pathology. However, evidence of FC related to self‐generated thoughts (mind‐wandering) stands in contrast with these assumptions, as FC may reflect thought patterns rather than functional architecture.MethodsMulti‐factor analysis (MFA) was used to investigate the reported content of self‐generated thoughts during high‐field (7T) rsfMRI in a repeated sample of 22 healthy individuals. To investigate the relationship between these experiences and FC, individual scores for each of these dimensions were compared with whole‐brain connectivity using the network‐based statistic (NBS) method.ResultsThis analysis revealed three dimensions of thought content: self‐referential thought, negative thoughts about one's surroundings, and thoughts in the form of imagery. A network of connections within the sensorimotor cortices negatively correlated with self‐generated thoughts concerning the self was observed (p = .0081, .0486 FDR).ConclusionThese results suggest a potentially confounding relationship between self‐generated thoughts and FC, and contribute to the body of research concerning the functional representation of mind‐wandering.
Dissociating self-generated volition from externally-generated motivation.
Insight into motivational processes may be gained by examining measures of willingness to exert effort for rewards, which have been linked to neuropsychiatric symptoms of anhedonia and apathy. However, while much work has focused on the development of models of motivation based on classic tasks of externally-generated levels of effort for reward, there has been less focus on the question of self-generated motivation or volition. We developed a task that aims to capture separate measures of self-generated and externally-generated motivation, with two task variants for physical and cognitive effort, and sought to test and validate this measure in two populations of healthy volunteers (N = 27 and N = 28). Similar to previous reports, a sigmoid function represented a better overall fit to the effort-reward data than a linear or Weibull model. Individual sigmoid function shapes were governed by two free parameters: bias (the amount of reward needed for effort initiation) and reward insensitivity (the amount of increase in reward needed to accelerate effort expenditure). For both physical and cognitive effort, bias was higher in the self-generated condition, indicating reduced self-generated volitional effort initiation, compared to externally-generated effort initiation, across effort domains. Bias against initial effort initiation in the self-generated condition was related to a specific dimensional measure of anticipatory anhedonia. For physical effort only, reward insensitivity was also higher in the self-generated condition compared to the externally-generated motivation condition, indicating lower self-generated effort acceleration. This work provides a novel objective measure of self-generated motivation that may provide insights into mechanisms of anhedonia and related symptoms.
Sub-millimeter variation in human locus coeruleus is associated with dimensional measures of psychopathology: An in vivo ultra-high field 7-Tesla MRI study.
The locus coeruleus (LC) has a long-established role in the attentional and arousal response to threat, and in the emergence of pathological anxiety in pre-clinical models. However, human evidence of links between LC function and pathological anxiety has been restricted by limitations in discerning LC with current neuroimaging techniques. We combined ultra-high field 7-Tesla and 0.4 × 0.4 × 0.5 mm quantitative MR imaging with a computational LC localization and segmentation algorithm to delineate the LC in 29 human subjects including subjects with and without an anxiety or stress-related disorder. Our automated, data-driven LC segmentation algorithm provided LC delineations that corresponded well with postmortem anatomic definitions of the LC. There was variation of LC size in healthy subjects (125.7 +/- 59.3 mm3), which recapitulates histological reports. Patients with an anxiety or stress-related disorder had larger LC compared to controls (Cohen's d = 1.08, p = 0.024). Larger LC was additionally associated with poorer attentional and inhibitory control and higher anxious arousal (FDR-corrected p's<0.025), trans-diagnostically across the full sample. This study combined high-resolution and quantitative MR with a mixture of supervised and unsupervised computational techniques to provide robust, sub-millimeter measurements of the LC in vivo, which were additionally related to common psychopathology. This work has wide-reaching applications for a range of neurological and psychiatric disorders characterized by expected LC dysfunction.
Neural correlates of rumination in major depressive disorder: A brain network analysis.
Patients with major depressive disorder (MDD) exhibit higher levels of rumination, i.e., repetitive thinking patterns and exaggerated focus on negative states. Rumination is known to be associated with the cortical midline structures / default mode network (DMN) region activity, although the brain network topological organization underlying rumination remains unclear. Implementing a graph theoretical analysis based on ultra-high field 7-Tesla functional MRI data, we tested whether whole brain network connectivity hierarchies during resting state are associated with rumination in a dimensional manner across 20 patients with MDD and 20 healthy controls. Applying this data-driven approach we found a significant correlation between rumination tendency and connectivity strength degree of the right precuneus, a key node of the DMN. In order to interrogate this region further, we then applied the Dependency Network Analysis (DEPNA), a recently developed method used to quantify the connectivity influence of network nodes. This revealed that rumination was associated with lower connectivity influence of the left medial orbito-frontal cortex (MOFC) cortex on the right precuneus. Lastly, we used an information theory entropy measure that quantifies the cohesion of a network's correlation matrix. We show that subjects with higher rumination scores exhibit higher entropy levels within the DMN i.e. decreased overall connectivity within the DMN. These results emphasize the general DMN involvement during self-reflective processing related to maladaptive rumination in MDD. This work specifically highlights the impact of the MOFC on the precuneus, which might serve as a target for clinical neuromodulation treatment.
Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder.
Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p
Addictions NeuroImaging Assessment (ANIA): Towards an integrative framework for alcohol use disorder.
Alcohol misuse and addiction are major international public health issues. Addiction can be characterized as a disorder of aberrant neurocircuitry interacting with environmental, genetic and social factors. Neuroimaging in alcohol misuse can thus provide a critical window into underlying neural mechanisms, highlighting possible treatment targets and acting as clinical biomarkers for predicting risk and treatment outcomes. This neuroimaging review on alcohol misuse in humans follows the Addictions Neuroclinical Assessment (ANA) that proposes incorporating three functional neuroscience domains integral to the neurocircuitry of addiction: incentive salience and habits, negative emotional states, and executive function within the context of the addiction cycle. Here we review and integrate multiple imaging modalities focusing on underlying cognitive processes such as reward anticipation, negative emotionality, cue reactivity, impulsivity, compulsivity and executive function. We highlight limitations in the literature and propose a model forward in the use of neuroimaging as a tool to understanding underlying mechanisms and potential clinical applicability for phenotyping of heterogeneity and predicting risk and treatment outcomes.